Preparation of halogenated 4-aminophenols

ABSTRACT

The present invention relates to halogenated 4-aminophenols and to halogenated 4-(phenyldiazenyl)phenols, to a process for their preparation and to the use of the halogenated 4-hydroxyphenols for preparing active ingredients, especially in pharmaceuticals and agrochemicals.

There is therefore a need to provide a process which enables thepreparation of halogenated 4-aminophenols in good yields and in a simplemanner.

SUMMARY

The invention relates to a process for preparing a compound of theformula (I):

wherein

m is 0, 1, 2 or 3 and

n is 1, 2, 3 or 4,

where the sum of

m+n is a maximum of 4, and

R¹ is hydrogen, C₁-C₁₂-alkyl or C₅-C₁₅-arylalkyl and

R² is in each case independently C₁-C₁₂-fluoroalkyl,C₁-C₁₂-fluoroalkylthio or C₁-C₁₂-fluoroalkoxy and

Hal is in each case independently bromine, chlorine or fluorine.

The process involves the steps of A1, converting compounds of theformula (II)

-   -   in which    -   p is 0, 1, 2 or 3 and    -   R³ is in each case independently fluorine, chlorine, bromine,        iodine, cyano, thiocyanato, hydroxysulphonyl or alkali metal        salts thereof, nitro, C₁-C₁₂-alkyl, C₁-C₁₂-fluoroalkyl,        C₁-C₁₂-fluoroalkyoxy, C₁-C₁₂-fluoroalkylthio, C₁-C₁₂-alkoxy,        C₁-C₁₂-alkoxycarbonyl, di(C₁-C₁₂-alkyl)amino, C₄-C₁₄-aryl or        C₅-C₁₅-arylalkyl    -   to diazonium salts of the formula (III)

-   -   in which An⁻ is the anion of an acid and    -   A2) reacting    -   the diazonium salts of the formula (III) with compounds of the        formula (IV)

-   -   in which    -   m, n, Hal and R² are each as defined under the formula (I)    -   in the presence of a base to give compounds of the formula (V)

-   -   and    -   B) converting the compounds of the formula (V) with a reducing        agent to a compound of the formula (I) that has R¹ is hydrogen,        thereby forming at least one compound of formula (I).

In one embodiment, the invention relates to a compound of the formula(I):

wherein

m is 0, 1, 2 or 3 and

n is 1, 2, 3 or 4,

m+n is a maximum of 4, and

R¹ is hydrogen, C₁-C₁₂-alkyl or C₅-C₁₅-arylalkyl and

R² is in each case independently C₁-C₁₂-fluoroalkyl,C₁-C₁₂-fluoroalkylthio or C₁-C₁₂-fluoroalkoxy and

Hal is in each case independently bromine, chlorine or fluorine,

wherein the compound of formula (I) excludes a compound selected fromthe group consisting of 4-amino-3,5-difluorophenol,4-amino-2,5-difluorophenol, 4-amino-2,6-difluorophenol,4-amino-2-chloro-6-fluorophenol, 4-amino-2-chloro-3-fluorophenol,4-amino-2-chloro-5-fluorophenol, 4-amino-2-bromo-5-fluorophenol,4-amino-2-fluorophenol, 4-amino-3-fluorophenol,4-amino-2-(trifluoromethyl)phenol,4-amino-5-chloro-2-(trifluoromethyl)phenol,4-amino-2-chloro-6-(trifluoromethyl)phenol ot4-amino-3-(trifluoromethyl)phenol.

In another embodiment, the invention relates to a composition comprisinga compound of the formula (V),

wherein the compound of formula (V) excludes a compound selected fromthe group consisting of 3,5-difluoro-4-phenylazophenol,3-fluoro-4-phenylazophenol, 3-fluoro-4-(4′-nitrophenylazo) phenol,3-fluoro-4-(3′-nitrophenylazo)phenol,3-fluoro-4-(4′-thiocyanatophenylazo)phenol,3-fluoro-4-(4′-sulphophenylazo)phenol, ethyl4-(2′-fluoro-4′-hydroxyphenylazo)benzoate,2-fluoro-4-(4′-fluorophenylazo) phenol,2-fluoro-4-(3′-fluorophenylazo)phenol,2-fluoro-4-(4′-sulphophenylazo)phenol, ethyl4-(3′-fluoro-4′-hydroxyphenylazo)benzoate,2,3-difluoro-4-(4′-iodophenylazo) phenol,2,3-difluoro-4-(4′-sulphophenylazo) phenol and2,6-difluoro-4-(2′-bromophenylazo)phenol,3-(trifluoromethyl)-4-(phenylazo)phenol and3-(trifluoromethyl)-4-(4′-sodium sulphonate phenylazo)phenol, andcombinations thereof.

The invention also relates to methods for using the above-mentionedcompounds.

These and other features, aspects, and advantages of the presentinvention will become better understood with reference to the followingdescription and appended claims.

DESCRIPTION

Other than in the operating examples or where otherwise indicated, allnumbers or expressions referring to quantities of ingredients, reactionconditions, and the like, used in the specification and claims are to beunderstood as modified in all instances by the term “about.” Variousnumerical ranges are disclosed in this patent application. Because theseranges are continuous, they include every value between the minimum andmaximum values. Unless expressly indicated otherwise, the variousnumerical ranges specified in this application are approximations.

A process has now been found for preparing compounds of the formula (I)

in whichm is 0, 1, 2 or 3 andn is 1, 2, 3 or 4,where the sum ofm+n is a maximum of 4, andR¹ is hydrogen, C₁-C₁₂-alkyl or C₅-C₁₅-arylalkyl andR² is in each case independently C₁-C₁₂-fluoroalkyl, C₁-C₁₂—fluoroalkylthio or C₁-C₁₂-fluoroalkoxy andHal is in each case independently bromine, chlorine or fluorine,

characterized in that

in a step A1),

compounds of the formula (II)

in whichp is 0, 1, 2 or 3 andR³ is in each case independently fluorine, chlorine, bromine, iodine,cyano, thiocyanato, hydroxysulphonyl or alkali metal salts thereof,nitro, C₁-C₁₂-alkyl, C₁-C₁₂-fluoroalkyl, C₁-C₁₂-fluoroalkyoxy,C₁-C₁₂-fluoroalkylthio, C₁-C₁₂-alkoxy, C₁-C₁₂-alkoxycarbonyl,di(C₁-C₁₂-alkyl)amino, C₄-C₁₄-aryl or C₅-C₁₅-arylalkylare converted to diazonium salts of the formula (III)

in which An⁻ is the anion of an acid and

in a step A2),

the diazonium salts of the formula (III) are reacted with compounds ofthe formula (IV)

in which

m, n, Hal and R² are each as defined under the formula (I)

in the presence of base to give compounds of the formula (V)

and

in a step B),

the compounds of the formula (V) are converted using a reducing agent tothe compounds of the formula (I) in which R¹ is hydrogen and

optionally, in a step C),

these compounds are converted by O-alkylation to compounds of theformula (I) in which R¹ is C₁-C₁₂-alkyl.

This excludes the preparation of 4-amino-3,5-difluorophenol and4-amino-3-fluorophenol.

Optionally, in a step D),

the compounds of the formula (I) can be converted by reacting withcompounds of the formulae (VIIa) or (VIIb)

in which

-   R⁴ is 2,4-difluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl or    4-fluoro-3-chlorophenyl and-   R⁵ is optionally mono- or poly-chlorine- or -fluorine-substituted    phenyl to compounds of the formula (VIII)

in whichR¹, R², R⁴, Hal, n and m are each as defined above.Step D) may be carried out in a manner known per se, for example similarto that described in U.S. Pat. No. 4,851,535.Optionally, in a step E),

the compounds of the formula (VIII) can be converted by reacting withcompounds of the formula (IX)

in which

-   R⁶ is C₁-C₁₂-alkyl, C₅-C₁₅-arylalkyl or C₄-C₁₄-aryl

to compounds of the formula (X)

in which

R¹, R², R⁴, R⁶, Hal, n and m are each as defined above.

The reaction of the compounds of the formula (VII) with compounds of theformula (IX) to give compounds of the formula (X) may be effected, forexample, by heating the two reactants in an organic solvent, preferablyan aliphatic alcohol, for example methanol.

The compounds mentioned as exceptions for steps A) to C) are excluded inthe same manner for steps D) and E).

In the context of the invention, all radical definitions, parameters andillustrations above and listed herein below, in general or specifiedwithin areas of preference, i.e. the particular areas and areas ofpreference, may be combined as desired.

The term “alkyl” and “alkoxy” are in each case independently astraight-chain, cyclic, branched or unbranched alkyl and alkoxy radicalrespectively. The same applies to the nonaromatic moiety of an arylalkylradical.

C₁-C₄-Alkyl is, for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl and tert-butyl, and C₁-C₁₂-alkyl is additionally, forexample, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,neopentyl, 1-ethylpropyl, cyclohexyl, cyclopentyl, n-hexyl, n-heptyl,n-octyl, n-nonyl, n-decyl and n-dodecyl.

The term “fluoroalkyl,” “iluoroalkoxy” and “fluoroalkylthio” are in eachcase independently a straight-chain, cyclic, branched or unbranchedalkyl, alkoxy and alkylthio radical respectively, each of which issingly, multiply or fully substituted by fluorine atoms.

For example, C₁-C₁₂-fluoroalkyl is trifluoromethyl,2,2,2-trifluoroethyl, pentafluoroethyl, nonafluorobutyl,heptafluoroisopropyl, perfluorooctyl and perfluorododecyl.

For example, C₁-C₁₂-fluoroalkoxy is trifluoromethoxy,2,2,2-trifluoroethoxy, pentafluoroethoxy, nonafluorobutoxy,heptafluoroisopropoxy, perfluorooctoxy and perfluorododecoxy.

For example, C₁-C₁₂-fluoroalkylthio is trifluoromethylthio,2,2,2-tri-fluoroethylthio, pentafluoroethylthio, nonafluorobutylthio,heptafluoroisopropylthio, perfluorooctylthio and perfluorododecylthio.

“Aryl” is in each case independently a heteroaromatic radical having 5to 14 skeleton carbon atoms of which nil, one, two or three skeletoncarbon atoms per cycle, but at least one skeleton carbon atom in theentire molecule, may be substituted by heteroatoms selected from thegroup of nitrogen, sulphur and oxygen, and is preferably a carbocyclicaromatic radical having 6 to 14 skeleton carbon atoms.

In addition, the carbocyclic aromatic radical or heteroaromatic radicalmay be substituted by up to five identical or different substituents percycle which are selected from the group of fluorine, cyano, nitro,C₁-C₁₂-alkyl, C₁-C₁₂-fluoroalkyl, C₁-C₁₂-fluoroalkoxy,C₁-C₁₂-fluoroalkylthio, C₁-C₁₂-alkoxy, di(C₁-C₁₂-alkyl)amino.

“Arylalkyl” is in each case independently a straight-chain, cyclic,branched or unbranched alkyl radical as defined above, each of which maybe singly, multiply or fully substituted by aryl radicals as definedabove.

The preferred substitution patterns are defined herein below:

n is preferably 1 or 2,m is preferably 0 or 1,R¹ is preferably hydrogen or methyl, more preferably hydrogen,R² is preferably trifluoromethyl, trifluoromethoxy andtrifluoromethylthio,Hal is preferably bromine, chlorine or fluorine, and at least one Halradical is more preferably fluorine.

In compounds of the formula (II), p is preferably 0.

The process according to the invention is especially suitable forpreparing 4-amino-2,3-difluorophenol, 4-amino-2,5-difluorophenol,4-amino-2,6-difluorophenol, 4-amino-2-fluorophenol,4-amino-3-chloro-5-fluorophenol, 4-amino-3-chloro-2-fluorophenol,4-amino-5-chloro-2-fluorophenol, 4-amino-3-bromo-5-fluorophenol,4-amino-2-(trifluoromethoxy)phenol and4-amino-3-(trifluoromethoxy)phenol.

Many of the compounds of the formula (I) are novel and likewiseencompassed by the invention, although the following are excluded:4-amino-3,5-difluorophenol, 4-amino-2,5-difluorophenol,4-amino-2,6-difluorophenol, 4-amino-2-chloro-6-fluorophenol,4-amino-2-chloro-3-fluorophenol, 4-amino-2-chloro-5-fluorophenol,4-amino-2-bromo-5-fluorophenol, 4-amino-2-fluorophenol,4-amino-3-fluorophenol, 4-amino-2-(trifluoromethyl)phenol,4-amino-5-chloro-2-(trifluoromethyl)phenol,4-amino-2-chloro-6-(trifluoromethyl)phenol and4-amino-3-(trifluoromethyl)phenol.

Particularly preferred individual compounds of the formula (I) include:4-amino-2,3-difluorophenol, 4-amino-3-chloro-5-fluorophenol,4-amino-3-chloro-2-fluorophenol, 4-amino-5-chloro-2-fluorophenol,4-amino-3-bromo-5-fluorophenol, 4-amino-2-(trifluoromethoxy)phenol and4-amino-3-(trifluoromethoxy)phenol.

In step A1), the compounds of the formula (III) can be prepared fromcompounds of the formula (II) in a manner known per se. Advantageously,the compounds of the formula (II) are reacted with a nitrite source inthe presence of water and acid.

The acids used may be, for example, mineral acids such as hydrochloricacid, hydrobromic acid, sulphuric acid or tetrafluoroboric acid, or elseorganic sulphonic acids.

The nitrite source used may be, for example, the alkali metal nitrites,especially sodium nitrite or potassium nitrite, and also organicnitrites, especially tert-butyl nitrite or methyl nitrite. Preference isgiven to alkali metal nitrites which are preferably used dissolved inwater.

The molar ratio of protons of the acid used to compounds of the formula(II) may be, for example, 1 to 15, preferably 2 to 10 and morepreferably 2.5 to 6.5.

The molar ratio of compounds of the formula (II) to the nitrite sourcemay be, for example, 0.8 to 4, preferably 1.0 to 2.5 and more preferably1.05 to 1.5.

The reaction temperature in step A1) may be, for example, −20° C. to 40°C., preferably −10° C. to 20° C. and more preferably −5° C. to 10° C.;the reaction pressure may be, for example, 0.5 to 100 bar, preferablyambient pressure; the reaction time may be 10 min to 5 hours, preferably1 hour to 3 hours.

To convert the compounds of the formula (II), the procedure is, forexample, to initially charge the compounds of the formula (II) in waterand acid and subsequently add an aqueous solution of the alkali metalnitrite. On completion of the reaction time, an excess of alkali metalnitrite may be destroyed by adding a primary amino compound, for exampleurea or amidosulphuric acid.

The starting compounds of the formula (II) required for step A1) areknown from the literature or can be synthesized in a similar manner tothe literature.

In step A2), the compounds of the formula (III) obtained in step A1) arereacted with compounds of the formula (IV) in the presence of base togive compounds of the formula (V).

Suitable bases are in principle all bases which are more basic than thecompounds of the formula (IV), preferably by at least 2 pK units.

Preference is given to using alkali metal or alkaline earth metalhydroxides, carbonates and hydrogen carbonates, of which alkali metalhydroxides, such as sodium hydroxide in particular, are preferred.

The base may either be initially charged or added in the course of thereaction in such a way that the reaction medium remains alkaline.

The molar ratio of compounds of the formula (III) to compounds of theformula (IV) may be, for example, 0.3 to 5, preferably 0.5 to 2 and morepreferably 0.6 to 0.9.

The molar ratio of compounds of the formula (III) to base may be, forexample, 1 to 15, preferably 3 to 10 and more preferably 4 to 7.

The reaction temperature in step A2) may be, for example, −20° C. to 50°C., preferably 0° to 40° C. and more preferably 50 to 30° C., thereaction pressure, for example, 0.5 to 100 bar, preferably ambientpressure. In addition, the reaction time may be, for example, 10 min to15 hours, preferably 3 to 5 hours.

The workup of the compounds of the formula (V) may be effected in amanner known per se by extraction and subsequent distillation, or, inthe case of compounds of the formula (V) which are solid at 30° C., byfiltration and crystallization.

The compounds of the formula (V) are likewise encompassed by theinvention as important intermediates, although the following areexcluded: 3,5-difluoro-4-phenylazophenol, 3-fluoro-4-phenylazophenol,3-fluoro-4-(4′-nitrophenylazo)phenol,3-fluoro-4-(3′-nitrophenylazo)phenol,3-fluoro-4-(4′-thiocyanatophenylazo)phenol,3-fluoro-4-(4′-sulphophenylazo)phenol, ethyl4-(2′-fluoro-4′-hydroxyphenylazo)benzoate,2-fluoro-4-(4′-fluorophenylazo)phenol,2-fluoro-4-(3′-fluorophenylazo)phenol,2-fluoro-4-(4′-sulphophenylazo)phenol, ethyl4-(3′-fluoro-4′-hydroxyphenylazo)benzoate,2,3-difluoro-4-(4′-iodophenylazo)phenol,2,3-difluoro-4-(4′-sulphophenylazo)phenol and2,6-difluoro-4-(2′-bromophenylazo)phenol,3-(trifluoromethyl)-4-(phenylazo)phenol and3-(trifluoromethyl)-4-(4′-sodium sulphonate phenylazo)phenol.

The compounds of the formula (IV) are known from the literature or canbe synthesized in a similar manner to the literature.

In step B), compounds of the formula (V) are converted by reduction tocompounds of the formula (I).

The reduction may be effected, for example, by reducing agents such assodium bisulphite, titanium(III) chloride or tin and hydrochloric acid.More advantageously, the reduction is carried out in the presence ofhydrogen and catalyst.

Preferred catalysts are, for example, metals or metal compounds,especially salts or complexes of nickel, palladium, platinum, cobalt,rhodium, iridium and ruthenium, and preference is given to metals suchas nickel or palladium. Metals are preferably used in finely dividedform, for example as Raney metal, or applied to a support material.

Particular preference is given to carrying out the reduction withhydrogen and palladium on carbon.

The reduction in step B) may be carried out, for example, at a reactiontemperature of 0° C. to 200° C., preferably at 10° C. to 80° C. and morepreferably at 20° C. to 40° C.

The partial hydrogen pressure in the reduction may be, for example, 0.1to 180 bar, preferably 0.5 to 50 bar and more preferably 1 to 3 bar.

Optionally and with preference, the reduction may be carried out in thepresence of solvents, as long as they are substantially inert under thereaction conditions selected.

Suitable solvents are, for example, aliphatic, alicyclic or aromatic,optionally halogenated hydrocarbons, for example benzine, benzene,toluene, xylene, chlorobenzene, dichlorobenzene, petroleum ether,hexane, cyclohexane, dichloromethane, chloroform or carbontetrachloride; ethers such as diethyl ether, diisopropyl ether, dioxane,tetrahydrofuran or ethylene glycol dimethyl ether or ethylene glycoldiethyl ether; alcohols, for example methanol, ethanol and isopropanolor mixtures of solvents.

In a particularly preferred embodiment, the reduction is carried out inthe presence of palladium on activated carbon and in the presence ofmethanol or ethanol at a partial hydrogen pressure of 1 to 3 bar.

The reaction time in the reduction may be 10 min to 100 hours,preferably 2 to 20 hours.

The workup of the compounds of the formula (I) in which R¹ is hydrogenmay be effected in a manner known per se by extraction and subsequentdistillation or, in the case of compounds of the formula (I) which aresolid at 30° C., by recrystallization.

Optionally, step C), the O-alkylation of compounds of the formula (I) inwhich R¹ is hydrogen, is undertaken.

Preference is given in this case to carrying out the reaction in thepresence of an inorganic base.

Suitable inorganic bases are in principle all bases which are more basicthan the compounds of the formula (I) in which R¹ is hydrogen,preferably by at least 3 pK units.

Preferred inorganic bases are alkali metal or alkaline earth metalcarbonates, hydrogencarbonates and hydroxides, and alsotetraalkylammonium hydroxides, of which preference is given to alkalimetal carbonates and hydroxides.

Suitable alkylating agents are in particular compounds of the formula(VI)

R¹-Act  (VI)

in which

R¹ is C₁-C₁₂-alkyl, C₅-C₁₅-arylalkyl and

Act is iodine, bromine, chlorine or a sulphonate.

Suitable solvents for carrying out the alkylation are in particularethers such as methyl tert-butyl ether, dioxane, tetrahydrofuran orethylene glycol dimethyl ether or ethylene glycol diethyl ether; amidessuch as N,N-dimethylformamide, N,N-dimethylacetamide,N-methylformanilide, N-methylpyrrolidone, N-methylcaprolactam orhexamethylphosphoramide; sulphoxides such as dimethyl sulphoxide,sulphones such as tetramethylenesulphone or mixtures of such organicsolvents.

The molar ratio of inorganic base to compounds of the formula (I) inwhich R¹ is hydrogen may be, for example, 0.3 to 5, preferably 0.5 to 3and more preferably 0.9 to 1.3.

The molar ratio of alkylating agents to compounds of the formula (I) inwhich R¹ is hydrogen may be, for example, 0.3 to 5, preferably 0.5 to 3and more preferably 0.9 to 1.8.

The reaction temperature in step C) may be, for example, −70° C. to 100°C., preferably −20 to 60° C. and more preferably 0 to 40° C.

The reaction time in step C) may be, for example, 10 min to 24 hours,preferably 1 to 8 hours.

In the inventive manner, the compounds of the formula (I), (VIII) and(X) are obtained in good yields starting from readily availablereactants. The compounds of the formula (I), (VII) and (X), and also thecompounds of the formula (V), are especially suitable for use in aprocess for preparing active ingredients in pharmaceuticals andagrochemicals, or intermediates thereof.

Preferred active ingredients of pharmaceuticals are those which are usedto treat chronic bronchitis, and preference is given to those which aredescribed in WO 03/08413 and PCT 03/02154.

The invention is further illustrated but is not intended to be limitedby the following examples in which all parts and percentages are byweight unless otherwise specified.

EXAMPLES Example 1 Preparation of 3,5-difluoro-4-(phenyldiazenyl)phenol

At 0° C., 108.2 g (1.16 mol) of aniline were dissolved with vigorousstirring in 500 g of 27% hydrochloric acid. Afterwards, at 5°-0° C.,95.2 g (1.38 mol) of sodium nitrite (dissolved in 283 ml of water) wereadded dropwise and the solution was stirred for another 60 minutes oncompletion of addition. Excess sodium nitrite was destroyed withamidosulphuric acid. In a further flask, 101.2 g (0.77 mol) of3,5-difluorophenol were dissolved in a solution of 182.8 g (4.57 mol) ofsodium hydroxide in 2281 ml of water, and precooled to 5° C. The abovefreshly prepared diazonium salt solution is added to this solution atsuch a rate that the internal temperature did not rise above 5° C.During the addition, the pH was monitored regularly. On completion ofaddition, the mixture was allowed to warm to room temperature, andstirred for a further 60 minutes, and the suspension was then adjustedto pH 4 using 2N HCl. The product was filtered off and washed repeatedlywith water. After the drying in a vacuum drying cabinet, 182 g(quantitative yield) of the desired orange-brown azo compound wereobtained.

EI-MS: m/z 234 [M]⁺

Example 2 Preparation of 4-amino-3,5-difluorophenol

20.4 g (0.09 mol) of 3,5-difluoro-4-(phenyldiazenyl)phenol from Example1 and 0.5 g of Pd/C (10%) were initially charged in 120 ml of methanol.The solution was degassed and aerated with hydrogen. The mixture wasstirred at room temperature under a 1 bar hydrogen atmosphere for 16hours. On completion of hydrogen uptake, the catalyst was filtered offand the filtrate concentrated on a rotary evaporator. The residue waschromatographed on silica gel (n-hexane/ethyl acetate, 3:1). Theresulting solid was stirred with n-hexane and dried. 7.6 g (60%) of4-amino-3,5-difluorophenol were obtained as a yellow-brown solid.

¹H NMR (400 MHz, CDCl₃): δ=3.40 (s, 2H, NH₂); 4.55 (s, 1H, OH); 6.39 (m,2H, Ar—H)

¹⁹F NMR (376.3 MHz, CDCl₃): δ=−130.5

EI-MS: m/z 145 [M]⁺

m.p.: 150-151° C.

Example 3 Preparation of 2,3-difluoro-4-(phenyldiazenyl)phenol

At 0° C., 27.3 ml (0.3 mol) of aniline were added dropwise with vigorousstirring to 140 ml of HCl (semiconc.). Afterwards, at 5°-0° C., 21.7 g(0.315 mol) of NaNO₂ (dissolved in 100 ml of water) were added dropwiseand, on completion of addition, the solution was stirred for another 20minutes.

In a further flask, 39 g (0.3 mol) of 2,3-difluorophenol were dissolvedin 300 ml of 2N NaOH and precooled to 0° C. The above freshly prepareddiazo solution was added to this solution at such a rate that theinternal temperature does not rise above 5° C. During the addition, thepH was monitored regularly and, if necessary, made alkaline again bymeans of Na₂CO₃. On completion of addition, the mixture was allowed towarm to room temperature, stirred for a further 30 minutes and then thesuspension was adjusted to pH 3-4 using 2N HCl. The product was filteredoff and washed repeatedly with water. After the drying in the vacuumdrying cabinet, 61 g (87%) of the desired bright yellow azo compoundwere obtained.

EI-MS: m/z 234 [M]⁺

Example 4 Preparation of 4-amino-2,3-difluorophenol

61 g (0.26 mol) of 2,3-difluoro-4-(phenyldiazenyl)phenol from Example 3and 1 g of Pd/C (10%) are initially charged in 800 ml of ethanol. Thesolution was degassed and aerated with hydrogen. The mixture was stirredat room temperature under a 1 bar hydrogen atmosphere for 18 hours. Oncompletion of hydrogen uptake, the catalyst was filtered off and thefiltrate was concentrated on a rotary evaporator, in the course of whichthe product already crystallized out. The resulting solid was filteredoff, washed with a little cold ethanol and dried under high vacuum for 4hours. 28 g (74%) of the desired compound were obtained as a light brownpowder.

¹H NMR (400 MHz, DMSO-d₆) δ=4.72 (s, 2H, NH₂), 6.39 (t, 1H, Ar—H), 6.51(t, 1H, Ar—H), 9.13 (s, 1H, OH);

EI-MS: m/z 145 [M]⁺

Example 5 Preparation of 2,5-difluoro-4-(phenyldiazenyl)phenol

At 0° C., 17.5 ml (0.19 mol) of aniline were added dropwise withvigorous stirring to 185 ml of HCl (semiconc.). Afterwards, at 50-0° C.,13.9 g (0.2 mol) of NaNO₂ (dissolved in 50 ml of water) were addeddropwise and, on completion of addition, the solution was stirred foranother 20 minutes.

In a further flask, 25 g (0.19 mol) of 2,5-difluorophenol were dissolvedin 190 ml of 2N NaOH and precooled to 0° C. The above freshly prepareddiazo solution was added to this solution at such a rate that theinternal temperature did not rise above 5° C. During the addition, thepH was monitored regularly and, if necessary, made alkaline again bymeans of Na₂CO₃. On completion of addition, the mixture was allowed towarm to room temperature, stirred for a further 30 minutes, and thesuspension was then adjusted to pH 3-4 using 2N HCl. The product wasfiltered off and washed repeatedly with water. After drying in a vacuumdrying cabinet at 50° C., 42 g (93%) of the desired orange-coloured azocompound were obtained.

EI-MS: m/z 234 [M]⁺

Example 6 Preparation of 4-amino-2,5-difluorophenol

42 g (0.18 mol) of 2,5-difluoro-4-(phenyldiazenyl)phenol from Example 5and 1 g of Pd/C (10%) were initially charged in 650 ml of ethanol. Thesolution was degassed and aerated with hydrogen. The mixture was stirredat room temperature under a 1 bar hydrogen atmosphere for 18 hours. Oncompletion of hydrogen uptake, the catalyst was filtered off and thefiltrate distilled under reduced pressure, and dried under high vacuumat 70° C. for 4 hours. The residue (24 g) was recrystallized fromethanol and dried. 15 g (60%) of 4-amino-2,5-difluorophenol are obtainedas orange-brown powder.

¹H NMR (400 MHz, DMSO-d₆) δ=4.68 (s, 2H, NH₂), 6.58 (m, 2H, Ar—H), 9.05(s, 1H, OH);

EI-MS: m/z 145 [M]⁺

Example 7 Preparation of 2-trifluoromethoxy-4-(phenyldiazenyl)phenol

At 0° C., 10.23 ml (0.11 mmol) of aniline were added dropwise withvigorous stirring to 50 ml of HCl (semiconc.). Afterwards, at 5°-0° C.,8.1 g (0.117 mol) of NaNO₂ (dissolved in 30 ml of water) were addeddropwise and, on completion of addition, the solution was stirred for afurther 20 minutes.

In a further flask, 20.0 g (0.12 mol) of 2-trifluoromethoxyphenol weredissolved in 140 ml of 2N NaOH and precooled to 0° C. The above freshlyprepared diazo solution was added to this solution at such a rate thatthe internal temperature did not rise above 5° C. During the addition,the pH was monitored regularly and, if necessary, made alkaline again bymeans of Na₂CO₃. On completion of addition, the mixture was allowed towarm to room temperature and stirred for a further 30 minutes, and thesuspension was then adjusted to pH 3-4 using 2N HCl. The product wasfiltered off with suction and washed repeatedly with water. After dryingin a vacuum drying cabinet, 26 g (81%) of the desired light brown azocompound were obtained.

Example 8 Preparation of 4-amino-2-trifluoromethoxyphenol

25 g (0.09 mol) of 2-trifluoromethoxy-4-(phenyldiazenyl)phenol fromExample 7 and 1 g of Pd/C (10%) were initially charged in 350 ml ofethanol. The solution was degassed and aerated with hydrogen. Themixture was stirred at room temperature under a 1 bar hydrogenatmosphere for 72 hours. On completion of hydrogen uptake, the catalystwas filtered off and the filtrate concentrated on a rotary evaporator,in the course of which the product already crystallizes out. Theresulting solid was filtered off with suction, washed with a little coldethanol and dried under high vacuum for 4 hours. 8.5 g (50%) of thedesired compound were obtained as a light brown powder.

¹H NMR (400 MHz, DMSO-d₆) δ=4.72 (s, 2H, NH₂), 6.42 (d, 1H, J=8.6 Hz,Ar—H), 6.5 (s, 1H, Ar—H), 6.72 (d, 1H, J=8.6 Hz, Ar—H), 8.9 (s, 1H, OH);

EI-MS: m/z 193 [M]⁺

Although the invention has been described in detail in the foregoing forthe purpose of illustration, it is to be understood that such detail issolely for that purpose and that variations can be made therein by thoseskilled in the art without departing from the spirit and scope of theinvention except as it may be limited by the claims.

1. A compound of the formula (I):

wherein m is 0, 1, 2 or 3 and n is 1, 2, 3 or 4, m+n is a maximum of 4,and R¹ is hydrogen, C₁-C₁₂-alkyl or C₅-C₁₅-arylalkyl and R² is in eachcase independently C₁-C₁₂-fluoroalkyl, C₁-C₁₂-fluoroalkylthio orC₁-C₁₂-fluoroalkoxy and Hal is in each case independently bromine,chlorine or fluorine; wherein the compound excludes a compound selectedfrom the group consisting of 4-amino-3,5-difluorophenol,4-amino-2,5-difluorophenol, 4-amino-2,6-difluorophenol,4-amino-2-chloro-6-fluorophenol, 4-amino-2-chloro-3-fluorophenol,4-amino-2-chloro-5-fluorophenol, 4-amino-2-bromo-5-fluorophenol,4-amino-2-fluorophenol, 4-amino-3-fluorophenol,4-amino-2-(trifluoromethyl)phenol,4-amino-5-chloro-2-(trifluoromethyl)phenol,4-amino-2-chloro-6-(trifluoromethyl)phenol ot4-amino-3-(trifluoromethyl)phenol, and combinations thereof.
 2. Acompound of the formula (V),

wherein R² is in each case independently C₁-C₁₂-fluoroalkyl,C₁-C₁₂-fluoroalkylthio or C₁-C₁₂-fluoroalkoxy, R³ is in each caseindependently fluorine, chlorine, bromine, iodine, cyano, thiocyanato,hydroxysulphonyl or alkali metal salts thereof, nitro, C₁-C₁₂-alkyl,C₁-C₁₂-fluoroalkyl, C₁-C₁₂-fluoroalkyoxy, C₁-C₁₂-fluoroalkylthio,C₁-C₁₂-alkoxy, C₁-C₁₂-alkoxycarbonyl, di(C₁-C₁₂-alkyl)amino, C₄-C₁₄-arylor C₅-C₁₅-arylalkyl, and Hal is in each case independently bromine,chlorine or fluorine, m is 0, 1, 2 or 3 and n is 1, 2, 3 or 4, where thesum of m+n is a maximum of 4; and wherein the compound of formula (V)excludes a compound selected from the group consisting of3,5-difluoro-4-phenylazophenol, 3-fluoro-4-phenylazophenol,3-fluoro-4-(4′-nitrophenylazo) phenol,3-fluoro-4-(3′-nitrophenylazo)phenol,3-fluoro-4-(4′-thiocyanatophenylazo)phenol,3-fluoro-4-(4′-sulphophenylazo)phenol, ethyl4-(2′-fluoro-4′-hydroxyphenylazo)benzoate,2-fluoro-4-(4′-fluorophenylazo) phenol,2-fluoro-4-(3′-fluorophenylazo)phenol,2-fluoro-4-(4′-sulphophenylazo)phenol, ethyl4-(3′-fluoro-4′-hydroxyphenylazo)benzoate,2,3-difluoro-4-(4′-iodophenylazo) phenol,2,3-difluoro-4-(4′-sulphophenylazo) phenol and2,6-difluoro-4-(2′-bromophenylazo)phenol,3-(trifluoromethyl)-4-(phenylazo)phenol and3-(trifluoromethyl)-4-(4′-sodium sulphonate phenylazo)phenol, andcombinations thereof.